Phase I study of recombinant human tumor necrosis factor

• Published in: Cancer chemotherapy and pharmacology Vol. 20; no. 3; pp. 223 - 229
• Main Authors: KIMURA, K, TAGUCHI, T, NIITANI, H, OTA, K, SAITO, T, SUGA, S, SUZUOKI, Y, WAKUI, A, YAMADA, K, URUSHIZAKI, I, OHNO, R, ABE, O, FURUE, H, HATTORI, T, ICHIHASHI, H, INOGUCHI, K, MAJIMA, H
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01-01-1987
• Subjects: Adult; Aged; Antineoplastic agents; Biological and medical sciences; Blood Cells - drug effects; Blood Pressure - drug effects; Clinical Trials as Topic; Drug Evaluation; Female; General aspects; Humans; Kidney - drug effects; Leukocyte Count; Liver - drug effects; Male; Medical sciences; Middle Aged; Neoplasms - drug therapy; Pharmacology. Drug treatments; Platelet Count; Recombinant Proteins - pharmacokinetics; Recombinant Proteins - therapeutic use; Recombinant Proteins - toxicity; Tumor Necrosis Factor-alpha - pharmacokinetics; Tumor Necrosis Factor-alpha - therapeutic use; Tumor Necrosis Factor-alpha - toxicity; Antineoplastic agent; Human; Treatment; Intravenous administration; Tumor necrosis factor; Toxicity; Single dose; Phase I trial; Advanced stage; Tumor; Pharmacokinetics
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/bf00570490

A phase I clinical and pharmacokinetic study of recombinant human tumor necrosis factor (rH-TNF) was conducted in a single dose schedule in 33 patients with advanced cancer. rH-TNF was given by i.v. infusion over 30 min with a starting dose of 1 x 10(5) units/m2. The dose was escalated up to 16 x 10(5) units/m2 according to the modified Fibonacci scheme. Toxic effects were similar but not identical to those reported with interferons and interleukin-2, and included fever, rigors, nausea and vomiting and anorexia in a non-dose-dependent manner, and hypotension, leukocytosis, thrombocytopenia and transient elevation of transaminases (SGOT and SGPT) in an approximately dose-dependent manner. DIC syndrome was observed in one patient who had received 16 x 10(5) units/m2. The dose-limiting toxicities were hypotension, thrombocytopenia and hepatotoxicity, and the maximum tolerated dose in a single i.v. infusion of rH-TNF appeared to be 12 x 10(5) units/m2 when thrombocytopenia and elevation of SGOT and SGPT were taken as the dose-limiting toxicities. However, if hypotension was included, the maximum safely tolerated dose appeared to be 5 x 10(5) units/m2.